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STIM1-mediated NFAT signaling synergizes with STAT1 to control T-bet expression and TH1 differentiation
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STIM1-mediated NFAT signaling synergizes with STAT1 to control T-bet expression and TH1 differentiation
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Journal Article
STIM1-mediated NFAT signaling synergizes with STAT1 to control T-bet expression and TH1 differentiation
2025
Overview
Stromal interaction molecule 1 (STIM1) is critical for store-operated Ca
2+
entry (SOCE) and T cell activation. T helper 1 (T
H
1) cells, which express T-bet (encoded by
TBX21
), mediate immunity to intracellular pathogens. Although SOCE is known to regulate other T
H
lineages, its role in Th1 differentiation remains unclear. Here, we report a patient with an intronic loss-of-function mutation in
STIM1
, which abolishes SOCE and causes immunodeficiency. We demonstrate that SOCE promotes nuclear factor of activated T cells (NFAT) binding to conserved noncoding sequence (CNS)-12 in the
TBX21
enhancer and enables NFAT to synergize with STAT1 to mediate
TBX21
expression. While SOCE-deficient CD4
+
T cells have reduced expression of
TBX21
in the absence of interleukin-12 (IL-12), their expression of IL-12 receptors β1 and β2 is increased, sensitizing them to IL-12 signaling and allowing IL-12 to rescue T-bet expression. Our study reveals that the STIM1-SOCE–NFAT signaling axis is essential for the differentiation of Th1 cells depending on the cytokine milieu.
Feske and colleagues show how STIM- and ORAI-dependent calcium activation of NFAT plus IFN–STAT1 signaling activates T-bet expression independently of IL-12 stimulation. This NFAT–STAT1 activation pathway is required for T
H
1 cell differentiation and protection against viral infections when IL-12 is missing.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
